2-phenoxyaniline derivatives

ABSTRACT

A 2-phenoxyaniline derivative represented by the formula: ##STR1## wherein R 1  is a hydrogen atom, an amino group or an NHCOR 3  group, R 2  is a halogen atom, an amino group, a cyano group, a C 1-6  alkyl group, a C 1-3  perfluoroalkyl group, an NHCOR 3  group, a CH 2  OR 4  group, an OCH 2  R 5  group or a COR 6  group, R 3  is a C 1-6  alkyl group, R 4  is a hydrogen atom or a C 1-6  alkyl group, R 5  is a hydrogen atom, a C 1-6  alkyl group, a C 1-5  aminoalkyl group, a C 2-7  alkoxy-carbonyl group or a carbamoyl group, and R 6  is a C 1-6  alkyl group or a C 3-8  cycloalkyl group which is unsubstituted or substituted by a halogen atom, an amino group, a cyano group or a straight or branched C 1-6  alkyl group; or a pharmaceutically acceptable salt thereof.

TECHNICAL FIELD

The present invention relates to phenoxyaniline derivatives orpharmaceutically acceptable salts thereof having an inhibitory action ona Na⁺ /Ca²⁺ exchange system.

BACKGROUND ART

Among prior art compounds which inhibit a Na⁺ /Ca²⁺ exchange systemselectively and prevent overload of Ca²⁺ in cells regarded as importantin the cell injury mechanism after ischemia or reperfusion, there areknown compounds having a quinazoline skeleton as described in JapanesePatent Kokai 7-41465. However, there is no report that the compoundshaving a phenoxyaniline skeleton as shown in the present invention havean inhibitory action on a Na⁺ /Ca²⁺ exchange system.

DISCLOSURE OF THE INVENTION

As a result of extensive researches on the compounds having aninhibitory action on a Na⁺ /Ca²⁺ exchange system, the present inventorshave found that some kind of compounds having a phenoxyaniline skeletonmeet said object, and the present invention has been accomplished basedon the findings.

That is, the present invention is directed to a 2-phenoxylanilinederivative represented by Formula (1): ##STR2## wherein R¹ is a hydrogenatom, an amino group or an NHCOR³ group, R² is a halogen atom, an amonogroup, a cyano group, a C₁₋₆ alkyl group, a C₁₋₃ perfluoroalkyl group,an NHCOR³ group, a CH₂ OR⁴ group, an OCH₂ R⁵ group or a COR⁶ group, R³is a C₁₋₆ alkyl group, R⁴ is a hydrogen atom or a C₁₋₆ alkyl group, R⁵is a hydrogen atom, a C₁₋₆ alkyl group, a C₁₋₅ aminoalkyl group, a C₂₋₇alkoxy-carbonyl group or a carbamoyl group, and R⁶ is a C₁₋₆ alkyl groupor a C₃₋₈ cycloalkyl group which is unsubstituted or substituted by ahalogen atom, an amino group, a cyano group or a C₁₋₆ alkyl group; or apharmaceutically acceptable salt thereof.

Furthermore, the present invention is directed to a pharmaceuticalcomposition containing the above-mentioned compound or thepharmaceutically acceptable salt thereof as an effective component.

Furthermore, the present invention is directed to a pharmaceuticalcomposition for the treatment or prevention of ischemic heart diseases,ischemic cerebral diseases or ischemic renal diseases containing theabove-mentioned compound or the pharmaceutically acceptable salt thereofas an effective component.

Furthermore, the present invention is directed to use of theabove-mentioned compound or the pharmaceutically acceptable salt thereoffor the manufacture of a pharmaceutical composition for the treatment orprevention of ischemic heart diseases, ischemic cerebral diseases orischemic renal diseases.

Furthermore, the present invention is directed to a method for thetreatment or prevention of ischemia heart diseases, ischemic cerebraldiseases or ischemic renal diseases which includes the step ofadministering a pharmacologically effective amount of theabove-mentioned compound or the pharmaceutically acceptable salt thereofto a human.

Furthermore, the present invention is directed to a pharmaceuticalcomposition for the protection of cells during thrombolytic therapy,angioplasty, bypass operation of coronary artery or organtransplantation containing the above-mentioned compound or thepharmaceutically acceptable salt thereof as an effective component.

Furthermore, the present invention is directed to use of theabove-mentioned compound or the pharmaceutically acceptable salt thereoffor the manufacture of a pharmaceutical composition for the protectionof cells during thrombolytic therapy, angioplasty, bypass operation ofcoronary artery or organ transplantation.

Furthermore, the present invention is directed to a method for theprotection of cells during thrombolytic therapy, angioplasty, bypassoperation of coronary artery or organ transplantation which includes thestep of administering a pharmacologically effective amount of theabove-mentioned compound or the pharmaceutically acceptable salt thereofto a human.

In the present invention, the halogen atom refers to a fluorine atom, achlorine atom, a bromine atom or an iodine atom.

The C₁₋₆ alkyl group refers to a straight or branched C₁₋₆ alkyl group,and specific examples thereof are a methyl group, an ethyl group, apropyl group, an isopropyl group, a butyl group, an isobutyl group, asec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group,a neopentyl group, a tert-pentyl group, a 1-methylbutyl group, a2-methylbutyl group, a 1,2-dimethylpropyl group, a hexyl group and anisohexyl group.

Specific examples of the C₁₋₃ perfluoroalkyl group are a trifluoromethylgroup and a pentafluoroethyl group.

The C₁₋₅ aminoalkyl group refers to a straight or branched C₁₋₅aminoalkyl group, and specific examples thereof are an aminomethylgroup, a 2-aminoethyl group, a 3-aminopropyl group, a 4-aminobutyl groupand a 5-aminopentyl group.

The C₂₋₇ alkoxycarbonyl group refers to a straight or branched C₂₋₇alkoxycarbonyl group, and specific examples thereof are amethoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group,an isopropoxycarbonyl group, a butoxycarbonyl group, anisobutoxycarbonyl group, a sec-butoxycarbonyl group, atert-butoxycarbonyl group, a pentyloxycarbonyl group, anisopentyloxycarbonyl group and a hexyloxycarbonyl group.

Specific examples of the C₃₋₈ cycloalkyl group are a cyclopropyl group,a cyclobutyl group, a cyclo-pentyl group and a cyclohexyl group.

Preferred phenoxyaniline derivatives of the present invention arecompounds of Formula (1) wherein R¹ is a hydrogen atom.

In the present invention, R² is preferably an OCH₂ R⁵ group (wherein R⁵is a hydrogen atom or a C₁₋₆ alkyl group), and more preferably an OCH₂R⁵ group (wherein R⁵ is a hydrogen atom or a C₁₋₂ alkyl group).

The phenoxyaniline derivatives of the present invention can be prepared,for example, according to the following preparation scheme (wherein R¹and R² are as defined above, R⁷ is a nitro group when R¹ is an aminogroup, or the same substituent as R¹ when R¹ is a substituent other thanan amino group, R⁸ is a nitro group when R² is an amino group, or thesame substituent as R² when R² is a substituent other than an aminogroup, and X is a fluorine atom or a chlorine atom). ##STR3##

That is, 4-(benzyloxy)phenol and a compound represented by Formula (2)are reacted in the presence of a base to give a compound represented byFormula (3). Examples of the base to be used herein are organic andinorganic bases such as potassium tert-butoxide, sodium hydroxide orsodium hydride. As the reaction solvent can be usedN,N-dimethylformamide or tetrahydrofuran, and the reaction temperatureis from room temperature to the reflux temperature.

Then, the compound represented by Formula (3) is reduced to give acompound of the present invention represented by Formula (1). As thereducing agent can be used herein iron-ammonium chloride, iron-aceticacid, palladium carbon-hydrogen, lithium aluminum hydride, nickelchloride-sodium borohydride, etc. As the reaction solvent can be usedherein water, methanol, ethanol, tetrahydrofuran, etc., and they can beused alone or in admixture. The reaction temperature is preferably from0° C. to the reflux temperature.

The phenoxyaniline derivative or the pharmaceutically acceptable saltthereof of the present invention is generally administered orally orparenterally to a human.

In case of oral administration, the phenoxyaniline derivative or thepharmaceutically acceptable salt thereof is mixed with a filler, adisintegrator, a binder, a lubricant, a coating agent, etc., to formgranules, powders, capsules or tablets, which then can be administered;and in case of parenteral administration, it can be administered in theform of injectable preparations, drip infusion preparations orsuppositories.

The above-mentioned pharmaceutical preparations can be produced by anordinary preparation method such as agitation granulation, fluidized bedgranulation or disintegration granulation.

Examples of the filler are mannitol, xylitol, sorbitol, glucose,sucrose, lactose and crystalline cellulose.

Examples of the disintegrator are low substituted hydroxypropylcellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium andcarboxymethyl cellulose sodium.

Examples of the binder are methyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, polyvinylpyrrolidone, gelatin, arabic gumand ethyl cellulose.

Examples of the lubricant are stearic acid, magnesium stearate andcalcium stearate.

If necessary, an anti-oxidant, a coating agent, a coloring agent, acorrigent, a surface active agent, a plasticizer and others can be addedto the pharmaceutical preparations.

The dose of the effective component of the pharmaceutical preparation inthe present invention can be varied depending on the age, body weight oradministration route, but it is usually from 0.1 to 1000 mg/day to anadult, which can be administered in a single dose or divided doses.

INDUSTRIAL APPLICABILITY

The compounds of the present invention have an inhibitory action on aNa⁺ /Ca²⁺ exchange system, thus, they prevent overload of Ca²⁺ in cells,are useful for the treatment or prevention of ischemic heart diseasessuch as myocardial infarction, ischemic cerebral diseases such ascerebral infarction, or ischemia renal diseases, and further useful forthe protection of cells during thrombolytic therapy, angioplasty, bypassoperation of coronary artery or organ transplantation.

BEST MODE OF CARRYING OUT THE INVENTION

The present invention is illustrated in more detail by the followingexamples and experiments. Furthermore, the structural formula whichrepresents the compounds prepared in Examples 1 to 24 is shown in Table1.

                  TABLE 1                                                         ______________________________________                                        Structural Formula                                                               -                                                                            #STR4##                                                                       Example                                                                       No. R.sup.1 R.sup.2                                                         ______________________________________                                         1     H           5-OCH.sub.3   hydrochloride                                   2 H 5-CH.sub.3   --                                                           3 H 5-CF.sub.3   --                                                           4 H 3-Cl hydrochloride                                                        5 H 4-CH.sub.3   --                                                           6 H 5-Cl   --                                                                 7 H 3-CH.sub.3 hydrochloride                                                  8 3-NH.sub.2 5-CF.sub.3 dihydrochloride                                       9 H 5-CO-c-C.sub.3 H.sub.5   --                                              10 4-NHCOCH.sub.3 5-Cl hydrochloride                                          11 H 5-COCH.sub.3   --                                                        12 5-NH.sub.2 4-CH.sub.3   --                                                 13 H 5-F hydrochloride                                                        14 H 3-NH.sub.2 dihydrochloride                                               15 H 5-CN hydrochloride                                                       16 3-NH.sub.2 5-CN dihydrochloride                                            17 H 5-OCH.sub.2 CH.sub.3 hydrochloride                                       18 H 5-OCH.sub.2 CH.sub.2 CH.sub.3   --                                       19 H 5-OCH.sub.2 CONH.sub.2 hydrochloride                                     20 H 5-OCH.sub.2 CO.sub.2 CH.sub.3 hydrochloride                              21 H 5-CH.sub.2 OH   --                                                       22 H 5-CH.sub.2 OCH.sub.3   --                                                23 H 5-NHCOCH.sub.2 CH.sub.2 CH.sub.3   --                                    24 H 5-OCH.sub.2 CH.sub.2 CH.sub.2 NH.sub.2 hydrochloride                   ______________________________________                                    

EXAMPLE 1

2-[4-(Benzyloxy)phenoxy]-5-methoxyaniline hydrochloride

(1) To a solution of 4-(benzyloxy)phenol (2.00 g, 10 mmol) inN,n-dimethylformamide (20 ml) was added potassium tert-butoxide (1.12 g,10 mmol), followed by stirring for 10 minutes. To the reaction solutionwas added 4-chloro-3-nitroanisole (1.88 g, 10 mmol), followed bystirring at 150° C. for 6 hours. After allowing to stand overnight, thereaction solution was poured into water and extracted with ethylacetate. After drying subsequent to washing with water and a saturatedaqueous sodium chloride solution, the solvent was evaporated underreduced pressure. The resulting crude crystals were recrystallized fromethanol to give 4-[4-(benzyloxy)phenoxy]-3-nitroanisole (2.13 g).

m.p. 88-89.5° C.

(2) To a solution of 4-[4-(benzyloxy)phenoxy]-3-nitroanisole (1.23 g,3.5 mmol) in ethanol (20 ml) were added an iron powder (0.90 g, 16.1mg-atom) and a solution of ammonium chloride (0.11 g, 2.1 mmol) in water(2 ml), followed by reflux for 3 hours. The insoluble matter wasfiltered, and the filtrate was poured into water, followed by extractionwith ethyl acetate. The organic layer was washed with water, then with asaturated aqueous sodium chloride solution and dried, and thereafter thesolvent was evaporated under reduced pressure. The residue was dissolvedin a small amount of ethyl acetate, and the resulting solution was,after addition of 4N-hydrogen chloride/acetic acid solution (2 ml),stirred for 30 minutes. The precipitating crystals were collected byfiltration and dried under reduced pressure to give the title compound(0.65 g).

m.p. 170-170.5° C.

The following compounds of Examples 2 to 16 were synthesized in the samemanner as in Example 1, and these instrumental measurement values wereshown below.

EXAMPLE 2

2-[4-(Benzyloxy)phenoxy]-5-methylaniline

m.p. 105.5-106.5° C.

EXAMPLE 3

2-[4-(Benzyloxy)phenoxy]-5-(trifluoromethyl)aniline

m.p. 100-101.5° C.

EXAMPLE 4

2-[4-(Benzyloxy)phenoxy]-3-chloroaniline hydrochloride

m.p. 176-177° C.

EXAMPLE 5

2-[4-(Benzyloxy)phenoxy]-4-methylaniline

m.p. 116.5-117.5° C.

EXAMPLE 6

2-[4-(Benzyloxy)phenoxy]-5-chloroaniline

m.p. 107-108° C.

EXAMPLE 7

2-[4-(Benzyloxy)phenoxy]-3-methylaniline hydrochloride

m.p. 193.5-194° C.

EXAMPLE 8

2-[4-(Benzyloxy)phenoxy-5-(trifluoromethyl)- 1 3-phenylenediaminedihydrochloride

m.p. 186.5-187° C.

EXAMPLE 9

2-[4-(Benzyloxy)phenoxy]-5-(cyclopropylcarbonyl)- aniline

m.p. 138-140° C.

EXAMPLE 10

4-Acetamido-2-[4-(benzyloxy)phenoxy]-5-chloroaniline hydrochloride

¹ H-NMR (DMSO-d₆, 200 MHz) δ (ppm); 1.99 (s, 3H), 5.08 (s, 2H), 7.05 (s,4H), 7.11 (s, 1H), 7.30-7.50 (m, 6H), 8.18 (bs, 3H), 9.41 (s, 1H).

EXAMPLE 11

5-Acetyl-2-[4-(benzyloxy)phenoxy]aniline

m.p. 135.5-136.5° C.

EXAMPLE 12

4-[4-(Benzyloxy)phenoxy]-6-methyl-1,3-phenylenediamine

¹ H-NMR (CDCl₃, 200 MHz) δ (ppm); 2.03 (s, 3H), 3.50 (bs, 4H), 5.00 (s,2H), 6.18 (s, 1H), 6.60 (s, 1H), 6.86 (s, 4H), 7.25-7.48 (m, 5H).

EXAMPLE 13

2-[4-(Benzyloxy)phenoxy]-5-fluoroaniline hydrochloride

m.p. 176.5-177° C.

EXAMPLE 14

2-[4-(Benzyloxy)phenoxy]-1,3-phenylenediamine dihydrochloride

m.p. 173-173.5° C.

EXAMPLE 15

2-[4-(Benzyloxy)phenoxy]-5-cyanoaniline hydrochloride

m.p. 170-171° C.

EXAMPLE 16

2-[4-(Benzyloxy)phenoxy]-5-cyano-1,3-phenylenediamine dihydrochloride

m.p. 160-161.50° C.

EXAMPLE 17

2-[4-(Benzyloxy)phenoxy-5-ethoxyaniline hydrochloride

(1) To a solution of 4-chloro-3-nitrophenol (5.00 g, 29 mmol) in acetone(50 ml) were added ethyl iodide (4.95 g, 32 mmol) and potassiumcarbonate (4.37 g, 32 mmol), followed by stirring at room temperaturefor 20 hours. After filtration of the insoluble matter, the filtrate wassubjected to evaporation under reduced pressure to remove the solvent,and the residue was purified by silica gel column chromatography(eluent; chloroform) to give 4-ethoxy-1-chloro-2-nitrobenzene (5.71 g).

(2) The title compound was obtained from 4-(benzyloxy)phenol and4-ethoxy-1-chloro-2-nitrobenzene in the same manner as in Example 1.

m.p. 164-164.5° C.

The following compounds of Examples 18 to 20 were synthesized in thesame manner as in Example 1, and these instrumental measurement valueswere shown below.

EXAMPLE 18

2-[4-(Benzyloxy)phenoxy-5-propoxyaniline

m.p. 103-103.5° C.

EXAMPLE 19

3-Amino-4-[4-(benzyloxy)phenoxy]phenoxy-acetamide hydrochloride

m.p. 198.5-199.5° C.

EXAMPLE 20

Methyl 3-amino-4-[4-(benzyloxy)-phenoxy]phenoxyacetate hydrochloride

m.p. 179-180° C.

EXAMPLE 21

3-Amino-4-[4-(benzyloxy)phenoxy]benzyl alcohol

(1) 4-[4-(Benzyloxy)phenoxy]-3-nitro-benzaldehyde was obtained from4-(benzyloxy)phenol and 4-chloro-3-nitrobenzaldehyde in the same manneras in Example 1(1).

m.p. 111-112.5° C.

(2) To a solution of 4-[4-(benzyloxy)-phenoxy]-3-nitrobenzaldehyde (2.48g, 7.1 mmol) in ethanol (100 ml) was added sodium borohydride (0.27 g,7.3 mmol), followed by stirring at room temperature for 2 hours. Thereaction solution was poured into water and extracted with ethylacetate. The solvent was dried and evaporated under reduced pressure.The residue was purified by silica gel column chromatography [eluent;chloroform - ethyl acetate (4:1)] to give4-[4-(benzyloxy)phenoxy]-3-nitrobenzyl alcohol (2.48 g).

m.p. 72-73° C.

(3) The title compound was obtained from4-[4-(benzyloxy)phenoxy]-3-nitrobenzyl alcohol in the same manner as inExample 1(2).

m.p. 128-130° C.

EXAMPLE 22

2-[4-(Benzyloxy)phenoxy]-5-(methoxymethyl)aniline

(1) To a solution of 4-[4-(benzyloxy)-phenoxy]-3-nitrobenzyl alcohol(9.43 g, 26.9 mmol) in chloroform (60 ml) was added thionyl chloride (2ml), followed by stirring at room temperature for 6 hours. Afterallowing to stand overnight, the reaction solution was washed with waterand dried, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography [eluent;hexane - chloroform (1:1)] to give4-[4-(benzyloxy)-phenoxy]-3-nitrobenzyl chloride (7.63 g).

m.p. 106-107° C.

(2) 60% Oily sodium hydride (0.22 g, 5.5 mmol) was added to methanol (50ml) under ice-cooling, and after stirring at room temperature for 30minutes, 4-[4-(benzyloxy)phenoxy]-3-nitrobenzyl chloride (1.00 g, 2.7mmol) was added thereto, followed by stirring for 3 hours. The reactionsolution was poured into water and extracted with ethyl acetate. Afterdrying, the solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography [eluent;hexane - chloroform (1:1)] to give1-[4-benzyloxy)phenoxy]-4-(methoxymethyl)-2-nitrobenzene (0.92 g).

(3) The title compound was obtained from 1-[4-(benzyloxy)phenoxy]-4-(methoxymethyl)-2-nitrobenzene in the samemanner as in Example 1(2).

m.p. 79.5-81° C.

EXAMPLE 23

N-[3-Amino-4-[4-(benzyloxy)phenoxy]phenyl]-butyramide

(1) To a solution of 4-chloro-3-nitroaniline (3.45 g, 30 mmol) inchloroform (100 ml) was added butyric anhydride (5 ml), followed bystirring at room temperature for 2 hours. After allowing to standovernight, a saturated aqueous sodium carbonate solution was added,followed by stirring for 30 minutes. The organic layer was separated anddried, the solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography [eluent;hexane - chloroform (1:1)] to give N-(4-chloro-3-nitrophenyl)butyramide(4.66 g).

(2) The title compound was obtained from 4-(benzyloxy)phenol andN-(4-chloro-3-nitrophenyl)-butyramide in the same manner as in Example1.

m.p. 122.5-123.50° C.

EXAMPLE 24

3- [3-Amino-4-[4-(benzyloxy)phenoxy]phenoxy]-propylamine hydrochloride

(1) To a solution of 4-chloro-3-nitrophenol (5.00 g, 29 mmol) inN,N-dimethylformamide (100 ml) were added N-(3-bromopropyl)phthalimide(9.27 g, 35 mmol) and potassium carbonate (4.93 g, 36 mmol), followed bystirring at 60° C. for 6 hours. After allowing to stand overnight, thereaction solution was poured into water, and the insoluble matter wascollected by filtration and washed with ethyl acetate and dried underreduced pressure to giveN-[3-(4-chloro-3-nitrophenoxy)-propyl]phthalimide (7.78 g).

(2) N-[3-[4-[4-(Benzyloxy)phenoxy]-3-nitrophenoxy]propyl]phthalimide wasobtained from 4-(benzyloxy)phenol andN-[3-(4-chloro-3-nitrophenoxy)-propyl]phthalimide in the same manner asin Example 1(1).

m.p. 140-141° C.

(3) To a solution ofN-[3-[4-[4-(benzyloxy)-phenoxy]-3-nitrophenoxy]propyl]phthalimide (2.06g, 3.9 mmol) in methanol (60 ml) was added hydrazine monohydrate (2 ml),followed by stirring for 3 hours. After allowing to stand overnight, thereaction solution was poured into water and extracted with chloroform.After drying, the solvent was evaporated under reduced pressure, and theresulting residue was dissolved in a small amount of ethyl acetate. Tothis solution was added 4N hydrogen chloride/ethyl acetate solution (2ml), followed by stirring at room temperature for 30 minutes. Theprecipitated crystals were collected by filtration and dried to give3-[4-[4-(benzyloxy)-phenoxy]-3-nitrophenoxy]propylamine hydrochloride(1.42 g).

m.p. 179-181° C.

(4) The title compound was obtained from3-[4-(benzyloxy)phenoxy]-3-nitrophenoxy]propylamine hydrochloride in thesame manner as in Example 1(2).

¹ H-NMR (DMSO-d₆, 200 MHz) δ (ppm); 2.02 (quint, J=6 Hz, 2H), 2.94(sext, J=6 Hz, 2H), 4.00 (t, J=6 Hz, 2H), 5.06 (s, 2H), 6.60 (dd, J=2, 9Hz, 1H), 6.76 (d, J=9 Hz, 1H), 6.88 (d, J=2 Hz, 1H), 6.92-7.08 (m, 4H),7.28-7.50 (m, 5H), 8.09 (bs, 3H).

EXPERIMENT

Inhibitors Action on a Na⁺ /Ca²⁺ Exchange System using MyosarcolemmalVesicles

Sarcolemmal vesicles which were prepared from the removed dogventricular muscles by referring to the method described in theliterature (L. R. Jones, Methods, Enzymol., 1988, 157, pp. 85) wereused.

A Na⁺ /Ca²⁺ exchange activity using the sarcolemmal vesicles wasmeasured by referring to the method described in the literature (K. D.Philipson, et al., J. Biol. Chem., 1980, 255, pp. 6880). First, thesarcolemmal vesicles were suspended in a sodium-containing solution [160mM sodium chloride, 20 mM hydrochloric acid (pH 7.4)] to make up to aprotein concentration of 1.5 mg/ml, and allowed to stand for an hour toload Na⁺ in the sarcolemmal vesicles. To 2.5 μl of the sarcolemmalvesicles was added 125 μl of a [⁴⁵ Ca]-calcium chloride solution [20 μM[⁴⁵ Ca]-calcium chloride, 160 mM potassium chloride and 20 mM Mops-Tris(pH 7.4)], and after 10 seconds, 900 μl of an ice-cooled lanthanumchloride solution [10 mM lanthanum chloride, 160 mM potassium chlorideand 20 mM Mops-Tris (pH 7.4)] was added. The sarcolemmal vesicles wererecovered on a nitrocellulose filter by suction filtration and washedthree times with 900 μl of a lanthanum chloride solution. Theconcentration of Ca²⁺ uptake in the sarcolemmal vesicles was determinedby measuring a ⁴⁵ Ca radioactivity by a scintillator. In addition, a Na⁺/Ca²⁺ exchange activity-independent Ca²⁺ uptake in the sarcolemmalvesicles was determined by carrying out the same procedure using apotassium-containing solution [160 mM potassium chloride, 20 mMTris-hydrochloric acid (pH 7.4)] instead of the sodium-containingsolution.

The test compound was used as a dimethyl sulfoxide solution thereof, andits inhibitory effect was evaluated in comparison with thevehicle-treated group. The IC₅₀ value was determined from a doseinhibition curve of the test compound by using the minimum squaremethod. The results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Test Compounds  IC.sub.50  (μM)                                            ______________________________________                                         1              1.1                                                             14 8.2                                                                        17 2.5                                                                        19 14.0                                                                       20 2.8                                                                      ______________________________________                                    

What is claimed is:
 1. A 2-phenoxyaniline derivative represented byFormula (1): ##STR5## wherein R¹ is a hydrogen atom, an amino group oran NHCOR³ group, R² is a halogen atom, an amino group, a cyano group, aC₁₋₆ alkyl group, a C₁₋₃ perfluoroalkyl group, an NHCOR³ group, a CH₂OR⁴ group, an OCH₂ R⁵ group or a COR⁶ group, R³ is a C₁₋₆ alkyl group,R⁴ is a hydrogen atom or a C₁₋₆ alkyl group, R⁵ is a hydrogen atom, aC₁₋₆ alkyl group, a C₁₋₅ aminoalkyl group, a C₂₋₇ alkoxy-carbonyl groupor a carbamoyl group, and R⁶ is a C₁₋₆ alkyl group or a C₃₋₈ cycloalkylgroup which is unsubstituted or substituted by a halogen atom, an aminogroup, a cyano group or a C₁₋₆ alkyl group; or a pharmaceuticallyacceptable salt thereof.
 2. The 2-phenoxyaniline derivative or thepharmaceutically acceptable salt thereof according to claim 1, whereinR¹ in Formula (1) is a hydrogen atom.
 3. The 2-phenoxyaniline derivativeor the pharmaceuticallyacceptable salt thereof according to claim 1,wherein in Formula (1) R¹ is a hydrogen atom and R² is an OCH₂ R⁵ groupin which R⁵ is a hydrogen atom or a C₁₋₆ alkyl group.
 4. Apharmaceutical composition containing the 2-phenoxyaniline derivative orthe pharmaceutically acceptable salt thereof according to claim 1 as aneffective component.
 5. An inhibitor of a Na⁺ /Ca²⁺ exchange systemcontaining the 2-phenoxyaniline derivative or the pharmaceuticallyacceptable salt thereof according to claim 1 as an effective component.6. A pharmaceutical composition for the treatment of ischemic heartdiseases, ischemic cerebral diseases or ischemic renal diseasescontaining the 2-phenoxyaniline derivative or the pharmaceuticallyacceptable salt thereof according to claim 1 as an effective component.7. A method for the treatment of ischemic heart diseases, ischemiccerebral diseases or ischemic renal diseases which includes the step ofadministering a pharmacologically effective amount of the2-phenoxyaniline derivative or the pharmaceutically acceptable saltthereof according claim 1 to a human.
 8. A pharmaceutical compositionfor the protection of cells during thrombolytic therapy, angioplasty,bypass operation of coronary artery or organ transplantation containingthe 2-phenoxyaniline derivative or the pharmaceutically acceptable saltthereof according to claim 1 as an effective component.
 9. A method forthe protection of cells during thrombolytic therapy, angioplasty, bypassoperation of coronary artery or organ transplantation which includes thestep of administering a pharmacologically effective amount of the2-phenoxyaniline derivative or the pharmaceutically acceptable saltthereof according to claim 1 to a human.